He attended the University of Kansas on an athletic scholarship. He was named a NCAAAll-Americacross-country runner three times and in 1960 he won the individual title in the Big Eight cross-country championship. The University of Kansas track team won the 1959 and 1960 outdoor national championships while Mills was on the team.

Mills was a virtual unknown. He had finished second in the U.S. Olympic trials. His time in the preliminaries was a full minute slower than Clarke's. Clarke set the tone of the race. His tactic of surging every other lap appeared to be working. Halfway through the race, only four runners were still with Clarke: Mohammed Gammoudi of Tunisia, Mamo Wolde of Ethiopia, Kokichi Tsuburaya of Japan, and Mills. Tsuburaya, the local favorite, lost contact first, then Wolde. With two laps to go, only two runners were still with Clarke. On paper, it seemed to be Clarke's race. He had run a world record time of 28:15.6, while neither Gammoudi nor Mills had ever run under 29 minutes.

Mills and Clarke were running together with Gammoudi right behind as they entered the final lap. They were lapping other runners and, down the backstretch, Clarke was boxed in. He pushed Mills once, then again. Then Gammoudi pushed them both and surged into the lead as they rounded the final curve. Clarke recovered and began chasing Gammoudi while Mills appeared to be too far back to be in contention. Clarke failed to catch Gammoudi, but Mills pulled out to lane 4 and sprinted past them both. His winning time of 28:24.4 was almost 50 seconds faster than he had run before and set a new Olympic record for the event. No American had ever before won the 10,000 m, nor has any other American come seriously close until Galen Rupp took the silver in the 2012 London Olympics.

American television viewers were able to hear the surprise and drama as NBC expert analyst Dick Bank[6] screamed "Look at Mills! Look at Mills!" over the more sedate play-by-play announcer Bud Palmer, who seemed to miss what was unfolding.[7] For bringing that drama to the coverage, Bank was fired.[8]

After the race, Mills talked with Clarke and asked if he was straining as hard as he could on the final straightaway to the finish, to which Clarke replied, "Yes." Mills has stated that he tried to be relaxed during his final kick to the finish line and felt that helped him pass both Gammoudi and Clarke. Both Clarke and Mills ran the marathon at the 1964 Olympics after the 10,000 m event. Clarke finished in 9th place, and Mills finished in 14th, in a respectable 2:22:55.4, approximately two-and-a-half minutes behind Clarke and about 10 minutes behind winner Abebe Bikila.

Mills later set U.S. records for 10,000 m (28:17.6) and the three-mile run, and had a 5,000 m best of 13:41.4. In 1965, he and Gerry Lindgren both broke the world record for the six-mile run when they finished in a tie at the AAUNational Championships, running 27:11.6.[9]

Mills is the co-founder of the nonprofit group Running Strong for American Indian Youth with Eugene Krizek. The aim of Running Strong is to help American Indian people fulfill their basic needs -food, water, and shelter- while also helping their communities gain self-sufficiency and self-esteem. He now acts as a spokesperson for the group and travels the country speaking out for and on behalf of Native American communities.[10] Mills charity work also includes diabetes prevention and management education for adults and especially for youth. Being a diabetes patient himself Mills helps people with diabetes learn how to maintain a healthy lifestyle and improve their lives.[11]

In 1984, he was one of a select group of former American Olympians given the honor of carrying the Olympic flag into the Los Angeles Memorial Coliseum at the opening ceremony of the Games of the XXIII Olympiad.[13]

He has also been inducted into the National Distance Running Hall of Fame, the Kansas Hall of Fame, the South Dakota Hall of Fame, the San Diego Hall of Fame, and the National High School Hall of Fame.

In 2015, The President's Council on Fitness, Sports, and Nutrition awarded Mills the President's Council Lifetime Achievement Award, which is given each year to up to 5 individuals "whose careers have greatly contributed to the advancement or promotion of physical activity, fitness, sports, or nutrition nationwide." [18]

Mills was one of several athletes featured on the August 18, 2016 On Being program "Running as a Spiritual Practice." [19]

^Jim Thorpe won two gold medals in the 1912 Stockholm Olympics, but they were later taken away when it was learned that he had played two seasons of minor-league baseball prior to the Olympics (and marred his amateur status). In 1983 the two gold medals were reinstated.

^ ab"Marine Corps History Division". Marine Corps History Division, United States Marine Corps. August 13, 2008. Retrieved 2008-08-14. Then-1stLt William 'Billy' Mills, USMCR, wove through a field of lapped runners and passed the race favorite, Ron Clarke of Australia, to win the 10,000 meter race at the 1964 Olympic Games. His victory has been described as the biggest upset in the history of the Olympic 10,000-meter run (and one of the biggest of all time in any Olympic event). Mills is still the only American ever to win a gold medal in that event.